The purpose of the Cape Town Adolescent Antiretroviral Cohort (CTAAC) is to investigate chronic disease processes in perinatally HIV-infected South African adolescents. The focus is on four key domains: the impact of chronic HIV infection on development; the neuropsychiatric manifestations of HIV in adolescence; the development of chronic lung disease; and early markers of cardiovascular dysfunction. Throughout, the emphasis of this research is on understanding the interactions between chronic disease processes across organ systems. The proposal will enroll 520 perinatally-infected children ages 9-14 years established on antiretroviral therapy. We will follow these children with regular measures (including measures of physical and psychological development, clinical well-being, lung function, cardiovascular status, and emergent risk behaviours) at 6-monthly intervals over 36 months. A control group of 80 HIV-negative controls will be matched on age, gender and socioeconomic status, in order to collect normative data on key parameters. A nested substudy will provide intensive neuropsychiatric evaluation and neuroimaging over time (n=200 HIV-infected children with 50 HIV-negative controls). Analyses will document the prevalence and natural history of chronic disease measures in each of the three organ systems, and then examine the associations between neuropsychiatric, cardiovascular and pulmonary pathology. There are specific hypotheses that: (i) HIV-infected children who initiated ART at an early age and/or disease stage will have fewer sequelae of chronic disease, and will experience less progression in system-specific chronic disease processes (either neurological, pulmonary and cardiovascular); (ii) Children with poorly controlled HIV viraemia during follow-up will experience greater progression in system-specific chronic disease manifestations; and (iii) Children with chronic disease manifestations in one organ system are more likely to have multi-system involvement and shared risk factors. The CTAAC team is comprised of leading South African researchers in pediatric HIV, neuropsychiatry, pulmonology, cardiology and epidemiology, who have pioneered research into the health of HIV-infected children and adolescents in sub-Saharan Africa. CTAAC represents a critical opportunity to address innovative scientific questions and advance our understanding the long-term effects of chronic HIV disease in order to promote the health of perinatally-infected young people as they grow older around the world.